rs35544003

chr14-76439434-C-Achr14-76439434-C-Gchr14-76439434-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001379180.1(ESRRB):c.144C>A(p.Ile48=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0647 in 1,613,444 control chromosomes in the GnomAD database, including 4,914 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.076 (605 hom., cov: 33)
  • Exomes 𝑓: 0.063 (4309 hom.)
• Consequence: ESRRB NM_001379180.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.310

Genes affected

ESRRB (HGNC:3473): (estrogen related receptor beta) This gene encodes a protein with similarity to the estrogen receptor. Its function is unknown; however, a similar protein in mouse plays an essential role in placental development. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.23).
• BP6: Variant 14-76439434-C-A is Benign according to our data. Variant chr14-76439434-C-A is described in ClinVar as [Benign]. Clinvar id is 45001.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.31 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.245 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ESRRB	NM_001379180.1	c.144C>A	p.Ile48=	synonymous_variant	2/7	ENST00000644823.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ESRRB	ENST00000644823.1	c.144C>A	p.Ile48=	synonymous_variant	2/7		NM_001379180.1	P1

Frequencies

GnomAD3 genomes AF: 0.0762 AC: 11603 AN: 152184 Hom.: 601 Cov.: 33

Gnomad AFR AF: 0.0918

Gnomad AMI AF: 0.0603

Gnomad AMR AF: 0.0855

Gnomad ASJ AF: 0.0271

Gnomad EAS AF: 0.256

Gnomad SAS AF: 0.137

Gnomad FIN AF: 0.0526

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.0537

Gnomad OTH AF: 0.0626

GnomAD3 exomes AF: 0.0869 AC: 21504 AN: 247442 Hom.: 1338 AF XY: 0.0861 AC XY: 11597 AN XY: 134658

Gnomad AFR exome AF: 0.0902

Gnomad AMR exome AF: 0.0905

Gnomad ASJ exome AF: 0.0251

Gnomad EAS exome AF: 0.249

Gnomad SAS exome AF: 0.138

Gnomad FIN exome AF: 0.0570

Gnomad NFE exome AF: 0.0574

Gnomad OTH exome AF: 0.0681

GnomAD4 exome AF: 0.0635 AC: 92781 AN: 1461142 Hom.: 4309 Cov.: 36 AF XY: 0.0652 AC XY: 47392 AN XY: 726870

Gnomad4 AFR exome AF: 0.0905

Gnomad4 AMR exome AF: 0.0885

Gnomad4 ASJ exome AF: 0.0242

Gnomad4 EAS exome AF: 0.247

Gnomad4 SAS exome AF: 0.134

Gnomad4 FIN exome AF: 0.0590

Gnomad4 NFE exome AF: 0.0505

Gnomad4 OTH exome AF: 0.0721

GnomAD4 genome AF: 0.0764 AC: 11633 AN: 152302 Hom.: 605 Cov.: 33 AF XY: 0.0799 AC XY: 5950 AN XY: 74474

Gnomad4 AFR AF: 0.0921

Gnomad4 AMR AF: 0.0856

Gnomad4 ASJ AF: 0.0271

Gnomad4 EAS AF: 0.256

Gnomad4 SAS AF: 0.137

Gnomad4 FIN AF: 0.0526

Gnomad4 NFE AF: 0.0537

Gnomad4 OTH AF: 0.0619

Alfa AF: 0.0546 Hom.: 105

Bravo AF: 0.0757

Asia WGS AF: 0.195 AC: 676 AN: 3478

EpiCase AF: 0.0455

EpiControl AF: 0.0439

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 07, 2012	Ile27Ile in Exon 04 of ESRRB: This variant is not expected to have clinical sig nificance because it does not alter an amino acid residue, is not located within the splice consensus sequence, and has been identified in 8.1% (301/3718) of Af rican American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS; dbSNP rs35544003). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 09, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Autosomal recessive nonsyndromic hearing loss 35 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.23
Cadd	Benign	4.4
Dann	Benign	0.91

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs35544003; hg19: chr14-76905777; COSMIC: COSV55058640; COSMIC: COSV55058640;